EP2318569B1 - Method for anodic dehydrodimerisation of substituted phenols - Google Patents

Abstract

The invention relates to a process for preparing biaryl alcohols, in which anodic dehydrodimerization of substituted phenols is carried out in the presence of partially fluorinated and/or periluorinated mediators and a supporting electrolyte at a graphite electrode.

Description

The invention relates to a process for the preparation of biaryl alcohols, which is carried out by anodic dehydrodimerization of substituted phenols in the presence of partially and / or perfluorinated mediators and a conductive salt on a graphite electrode.

The method according to the invention makes it possible to use very inexpensive electrode materials, undivided cell structures and solvent-free methods. As mediators, e.g. 1,1,1,3,3,3-hexafluoroisopropanol or the much cheaper trifluoroacetic acid are used.

The workup and recovery of the desired biphenols is very simple.

Biaryls are known as such and are industrially produced and used. Compounds of this class of compounds are i.a. as backbones for ligands of great interest for stereoselective transformations. One possible approach to this class of substances is the electrochemical oxidative dimerization of phenols, which, however, is nonselective in electrolytes known to those skilled in the art. As an alternative to the electrochemical dimerization of phenols, iron (III) salts or other strong oxidizing agents are used.

G. Lesse and KS Feldman describe in Modern Arene Chemistry, Ed: D. Astruc, VCH-Wiley, Weinheim 2002, pages 479-538 in that, in some cases, this transformation can also be achieved under aerobic conditions by means of transition-metal catalysis. The disadvantage of this synthesis is the use of iron chloride, as this leads to numerous by-products. Furthermore, only strongly activated compounds can be reacted after these aerobic conditions.

Particularly favored and therefore frequently used substrates have annellated benzene rings or sterically demanding alkyl groups. As an example, the 2,2'-dihydroxy-1,1'-binaphthyl (BINOL) prepared from 2-naphthol can be considered here.

Attempts to 2,4-dimethylphenol (1) analogous to the textbook regulations of CE Rommel, Staatsexamensarbeit, Münster 2002 and generally by H. Lund, MM Baizer, Organic Electrochemistry: An Introduction and a Guide, 3rd Edition, Marcel Dekker, New York 1991, Chapter 22.III, 885-908 to subject an oxidative coupling, it is usually obtained as the main product not the desired ortho, ortho-linked product 2, but a derivative of Pummerer ketone (3). The formation of the tricyclic skeleton 3 is known for para-alkyl-substituted phenols and is also found in the synthesis of many natural products.

For several years, the anodic synthesis of biphenols, in particular of 3,3 ', 5,5'-tetramethyl-2,2'-biphenol (2), has been intensively studied by various electrochemical methods. In the most diverse electrolyte systems, direct conversion also showed a strong preference for the formation of the Pummerer ketone derivative (3). The desired dehydrodimer 2 was isolated only in 3-7% yield. IM Malkowsky, CE Rommel, K. Wedeking, R. Fröhlich, K. Bergander, M. Nieger, C. Quaiser, U. Griesbach, H. Pütter and SR Waldvogel described in Eur. J. Org. Chem. 2006, 241- 245 the formation of further unprecedented pentacyclic scaffolds. Further investigations revealed that free phenoxyl radicals are responsible for the formation of the Pummerer ketone. In order to achieve a specific linkage in the ortho positions, as of IM Malkowsky, R. Fröhlich, U. Griesbach, H. Pütter and SR Waldvogel in Eur. J. Inorg. Chem. 2006, 1690-1697 and from IM Malkowsky, U. Griesbach, H. Pütter and SR Waldvogel in Chem. Eur. J. 2006, 12, 7482-7488 described, a boron template developed. Like C. Rommel, IM Malkowsky, SR Waldvogel, H. Pütter and U. Griesbach in WO-A 2005/075709 described, the electrochemical implementation of this multi-stage sequence succeeds for a larger substrate width and also at larger scales. An additional disadvantage in addition to the high preparative effort resulted from the use of acetonitrile in the electrolyte.

Using boron-doped diamond electrodes (BDD), a direct anodic conversion could be found for 2,4-dimethylphenol as the sole substrate IM Malkowsky, U. Griesbach, H. Pütter and SR Waldvogel in Eur. J. Org. Chem. 2006, 4569-4572 ; and M. Malkowsky, SR Waldvogel, H. Pütter and U. Griesbach in WO-A 2006/077204 describe. The ratio of biphenol to Pummerer ketone is usually better than 18: 1. In order to avoid electrochemical burnup at the BDD anode, the phenolic coupling is only brought to a conversion of about 30%. Additional disadvantages of this method are the low stability of the BDD electrodes, their price and the lack of substrate width.

The object of the present invention is to provide a method with which the selective and efficient oxidative coupling of substituted phenols takes place without having to work in the presence of expensive electrode material. Preferably, the coupling of substituted phenols should take place in the ortho position.

This object is achieved by a process for the preparation of biaryl alcohols, wherein substituted aryl alcohols are anodically dehydrodimerisiert in the presence of partially and / or perfluorinated mediators and at least one conducting salt by means of a graphite electrode, wherein the OH group of the substituted aryl alcohols used directly on the aromatic sitting.

The process according to the invention is advantageous if the substituted aryl alcohols used are identical.

The process according to the invention is advantageous if the substituted aryl alcohols used can be mononuclear or polynuclear.

The process according to the invention is advantageous if the dimerization takes place ortho to the alcohol group of the substituted aryl alcohols.

The process according to the invention is advantageous if the mediators used are partially and / or perfluorinated alcohols and / or acids.

The process according to the invention is advantageous if 1,1,1,3,3,3-hexafluoroisopropanol or trifluoroacetic acid is used as mediators.

The process according to the invention is advantageous if the conductive salts used are those selected from the group consisting of alkali, alkaline earth metal, tetra (C ₁ -C ₆ -alkyl) ammonium salts.

The process according to the invention is advantageous if the counterions of the conducting salts are selected from the group consisting of sulfate, hydrogensulfate, alkyl sulfates, aryl sulfates, halides, phosphates, carbonates, alkyl phosphates, alkyl carbonates, nitrate, alcoholates, tetrafluoroborate, hexafluorophosphate and perchlorate.

The process according to the invention is advantageous if no further solvent is used for the electrolysis.

The process according to the invention is advantageous if a flow cell is used for the electrolysis.

The process according to the invention is advantageous when current densities of 1 to 1000 mA / cm ² are used.

The process according to the invention is advantageous if the electrolysis is carried out at temperatures in the range from -20 to 60 ° C. and normal pressure.

The process according to the invention is advantageous if 2,4-dimethylphenol is used as aryl alcohol.

For the purposes of the present invention, aryl alcohol is understood as meaning aromatic alcohols in which the hydroxyl group is bonded directly to the aromatic nucleus.

The aromatic, which is based on the aryl alcohol, may be mononuclear or polynuclear. The aromatic is preferably mononuclear (phenol derivatives) or binuclear (naphthol derivatives), in particular mononuclear. The aryl alcohols may also carry further substituents. These substituents are independently selected from the group of C ₁ -C ₁₀ -alkyl groups, halogens, C ₁ -C ₁₀ -alkoxy groups, interrupted by oxygen or sulfur alkylene or arylene radicals, C ₁ -C ₁₀ -alkoxycarboxyl, nitrile, nitro and C ₁ -C ₁₀ -alkoxycarbamoyl, particularly preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, trifluoromethyl, fluorine, chlorine, bromine, iodine, methoxy, ethoxy, methylene, ethylene, propylene, isopropylene, benzylidene, nitrile, Nitro, most preferably methyl, methoxy, methylene, ethylene, trifluoromethyl, fluorine and bromine. With the new process, a wide range of aryl alcohols can be used. Particularly preferred are electron-rich arenes such as mono- or polysubstituted phenols and naphthol (α- and β-) and substituted derivatives thereof, very particularly preferred are 4-alkyl and 2,4-dialkyl-substituted phenols.

Suitable substrates for the electrodimerization according to the present invention are in principle all aryl alcohols, provided that they are capable of dimerization due to their spatial structure and steric requirements. The aryl alcohols may be mononuclear, dinuclear, trinuclear or higher nuclear. Preferably, they are mononuclear or dinuclear, in particular mononuclear. Furthermore, the aryl alcohols preferably have an OH function.

After completion of the reaction, the electrolyte solution is worked up by general separation methods. For this purpose, the electrolyte solution is generally first distilled and recovered the individual compounds in the form of different fractions separately. Further purification can be carried out, for example, by crystallization, distillation, sublimation or chromatographic.

The preparation of the biaryl alcohol is carried out electrolytically, wherein the corresponding aryl alcohol is anodized. The process according to the invention is referred to below as electrodimerization. It has surprisingly been found that the biaryl alcohols are produced selectively and in high yield by the method according to the invention using mediators. Furthermore, it has been found that very inexpensive electrode materials, undivided cell structures and solvent-free methods can be used by the method according to the invention.

The workup and recovery of the desired biphenols is very simple. After completion of the reaction, the electrolyte solution is worked up by general separation methods. For this purpose, the electrolyte solution is generally first distilled and recovered the individual compounds in the form of different fractions separately. Further purification can be carried out, for example, by crystallization, distillation, sublimation or chromatographic.

Partially and / or perfluorinated alcohols and / or acids, preferably perfluorinated alcohols and carboxylic acids, very particularly preferably 1,1,1,3,3,3-hexafluoroisopropanol or trifluoroacetic acid, are used as mediators in the process according to the invention.

No additional solvents are required in the electrolyte.

The corresponding products can be obtained by short path distillation and precipitation NMR pure.

The electrolysis is carried out in the usual, known in the art electrolysis cells. Suitable electrolysis cells are known to the person skilled in the art. Preferably, one works continuously in undivided flow cells or discontinuously in beaker cells.

Particularly suitable are bipolar switched capillary gap cells or plate stack cells, in which the electrodes are designed as plates and are arranged plane-parallel as in Ullmann's Encyclopaedia of Industrial Chemistry, 1999 electronic release, Sixth Edition, VCH-Weinheim, Volumne and in Electrochemistry, Chapter 3.5 , special cell designs as well Chapter 5, Organic Electrochemistry, Subchapter 5.4.3.2 Cell Design is described.

The current densities at which the process is carried out are generally 1 to 1000, preferably 5 to 100 mA / cm ² . The temperatures are usually -20 to 60 ° C, preferably 10 to 60 ° C. In general, working at atmospheric pressure. Higher pressures are preferably used when operating at higher temperatures to avoid boiling of the co-solvents or mediators.

Suitable anode materials are, for example, noble metals such as platinum or metal oxides such as ruthenium or chromium oxide or mixed oxides of the type RuO _x TiO _x and diamond electrodes. Preference is given to graphite or carbon electrodes. According to the invention, a graphite electrode is used as the anode.

As the cathode material, for example, iron, steel, stainless steel, nickel or precious metals such as platinum and graphite or carbon materials and diamond electrodes come into consideration. The system is preferably graphite as the anode and cathode, graphite as the anode and nickel, stainless steel or steel as the cathode and platinum as the anode and cathode.

To carry out the electrolysis, the aryl alcohol compound is dissolved in a suitable solvent. The usual solvents known to the person skilled in the art, preferably solvents from the group of polar protic and polar aprotic solvents, are suitable. Particularly preferably, the aryl alcohol compound itself serves as a solvent and reagent.

Examples of polar aprotic solvents include nitriles, amides, carbonates, ethers, ureas, chlorinated hydrocarbons.

Examples of particularly preferred polar aprotic solvents include Actonitrile, dimethylformamide, dimethyl sulfoxide, propylene carbonate and dichloromethane. Examples of polar protic solvents include alcohols, carboxylic acids and amides.

Examples of particularly preferred polar protic solvents include methanol, ethanol, propanol, butanol, pentanol and hexanol. These may also be partially or completely halogenated, e.g. 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) or trifluoroacetic acid (TFA).

Optionally, the electrolysis solution is added to customary cosolvents. These are the inert solvents customary in organic chemistry with a high oxidation potential. Examples include its dimethyl carbonate, propylene carbonate, tetrahydrofuran, dimethoxyethane, acetonitrile or dimethylformamide. Conducting salts which are contained in the electrolysis solution are generally alkali metal, alkaline earth metal, tetra (C ₁ - to C ₆ -alkyl) ammonium, preferably tri (C ₁ - to C ₆ -alkyl) -methylammonium salts. Suitable counterions are sulfate, bisulfate, alkyl sulfates, aryl sulfates, halides, phosphates, carbonates, alkyl phosphates, alkyl carbonates, nitrate, alcoholates, tetrafluoroborate, hexafluorophosphate or perchlorate. Furthermore, the acids derived from the abovementioned anions are suitable as conductive salts.

Preference is given to methyltributylammonium methylsulfates (MTBS), methyltriethylammonium methylsulfate (MTES), methyltripropylmethylammonium methylsulfates, or tetrabutylammonium, tetrafluoroborate (TBABF).

Examples: (tables with conversions)

Table 1: Reaction of 2,4-dimethylphenol on graphite using HFIP ^[a] electrolyte T [° C] U _max [V] F [1 / mol] j [mA / cm ² ] A ^ISTD [%] ^b SA [%] ^b A ^isolated [%] ^b rückgew. Phenol [g] 15.9 g phenol / 1 g MTES / 9 mL HFIP 30 27 1.00 20 66 53 3.09 15.9 g phenol / 1 g MTES / 9 mL HFIP 30 22 0.77 20 51 49 4.03 15.9 g phenol / 1 g MTES / 9 mL HFIP 30 17 0.77 10 66 50 55 ^d 6.60 15.9 g phenol / 3 g MTES / 9 mL HFIP 30 8th 0.77 10 47 35 6.91 15.9 g phenol / 5 g MTES / 9 mL HFIP 30 10 0.77 10 53 38 6.40 15.9 g phenol / 1 g a / 9 mL HFIP 30 17 0.77 10 54 54 6.08 15.9 g of phenol / 1 g 30 13 0.77 5 49 35 49 ^c 6.93 MTES / 9 mL HFIP 15.9 g phenol / 1 g MTES / 4 mL HFIP 30 21 0.77 10 49 36 6.95 HFIP: 1,1,1,3,3,3-hexafluoroisopropanol Table 2: Reaction of 2,4-dimethylphenol on graphite using carboxylic acids electrolyte T [° C] Umax [V] F [1 / mol] j [mA / cm ² ] A ^ISTD [%] ^b SA [%] ^b A ^isolated [%] ^{b, d} rückgew. Phenol [g] 15.9 g phenol / 1 g MTES / 9 mL TFA 30 28 0.77 10 41 33 41 6.19 15.9 g phenol / 1 g MTES / 9 mL TFA 30 16 0.77 10 53 50 50 4.38 15.9 g phenol / 1 g MTES / 9 mL TFA 30 15 0.77 10 58 51 53 5.12 15.9 g phenol / 1 g MTES / 9 mL TFA 30 18 0.77 10 67 55 64 5.89 15.9 g phenol / 1 g MTES / 9 mL AcOH 30 35 0.77 10 25 17 7.62 15.9 g phenol / 1 g MTES / 9 mL heptafluorobutyric acid 50 35 0.77 10 TFA: trifluoroacetic acid; AcOH: acetic acid; Phenol: 2,4-dimethylphenol;
MTES: methyltriethylammonium methyl sulfate Table 3: Reaction of 2-bromo-4-methylphenol on graphite electrolyte T [° C] Umax [V] F per mole j [mA / cm ² ] A ^ISTD [%] ^b SA [%] ^b A ^isolated [%] ^{b, d} rückgew. Phenol [g] 20.02 g phenol / 1 g MTES / 9 mL HFIP 30 14 0.77 10 54 24 36 13.25 20.02 g phenol / 1 g MTES / 9 mL TFA 30 22 0.77 10 73 51 76 9.08 Phenol: 2-bromo-4-methylphenol; a: N, N-dimethylpyrrolidinium methylsulfate; b: yield considering the recovered phenol; c: isolation by crystallization from toluene and chromatographic; d: Isolation by crystallization from ⁱ PrOH: water and chromatographic.

Example 1: Anodic oxidation of 2,4-dimethylphenol on graphite electrodes with trifluoroacetic acid

In an undivided standard electrolysis cell with graphite anode and cathode (A = 9 cm ² ), the electrolyte consisting of 15.90 g (0.1301 mol, 53 wt .-%) of 2,4-dimethylphenol, 1.00 g (4.4 mmol, 3 wt. -%) Methyltriethylammoniummethylsulfat and 9 mL (44 wt .-%) submitted trifluoroacetic acid. Under galvanostatic conditions, an electrolysis is carried out at 30 ° C and a current density of 10 mA / cm ² . 9669 C (0.77 F / mol) are applied at a maximum clamping voltage of 18 V. After completion of the reaction, the electrolyte is transferred with toluene in a flask and subsequently removed by distillation trifluoroacetic acid and toluene at room pressure. Subsequently, 5.89 g of excess phenol are recovered by short path distillation at 4.5 × 10 ^-3 mbar. The reaction residue is taken up in 30 ml aqueous isopropanol ( ⁱ PrOH: H ₂ O = 4: 1). By overnight storage at 4 ° C crystallization of the product is achieved, which is obtained by filtration and washing with a little cold n-heptane (4.24 g). Additional product can be isolated from the filtrate by short column chromatographic purification on silica gel (CH: EE = 98: 2) (2.15 g). Overall, 6.39 g (0.026 mol, 64%), taking into account excess phenol in the yield, gives a slightly reddish, crystalline product.

Melting point: 133 ° C; R _F value (CH: EE = 95: 5): 0.33; ¹ H-NMR (400 MHz, CDCl ₃ ): δ = 2.29 (s, 12H, CH ₃ ), 4.84 (s, 2H, OH), 6.88 (s, 2H, 4-H), 7.01 (s, 2H, 6-H); ¹³ C-NMR (100 MHz, CDCl _3): δ = 16:15 (3-CH _3), 20:41 (5-CH _3), 122.23 (C-1), 125.17 (C-3), 128.51 (C-6) , 129.98 (C-5), 131.97 (C-4), 149.13 (C-2); HRMS: m / z calculated for [C ₁₆ H ₁₉ O ₂ ] ⁺ 243.1380, found 243.1389; MS (ESI +): m / z (%): 243.1 (100) [C ₁₆ H ₁₉ O _2] ^+.

Example 2: Anodic oxidation of 2-bromo-4-methylphenol on graphite electrodes

In an undivided standard electrolysis cell with graphite anode and cathode (A = 9 cm ² ), the electrolyte consisting of 20.02 g (0.107 mol, 53 wt .-%) of 2-bromo-4-methylphenol, 1.00 g (4.4 mmol, 3 wt. -%) Methyltriethylammoniummethylsulfat and 11 mL (44 wt .-%) submitted trifluoroacetic acid. Under galvanostatic conditions, an electrolysis is carried out at 30 ° C and a current density of 10 mA / cm ² . 7950 C (0.77 F / mol) are applied at a maximum clamping voltage of 22 V. After completion of the reaction, the electrolyte is transferred with toluene in a flask and subsequently removed by distillation trifluoroacetic acid and toluene at room pressure. Subsequently, 9.08 g of excess phenol are recovered by short path distillation at 5.0 × 10 ^-3 mbar. The reaction residue is taken up in 30 ml aqueous isopropanol ( ⁱ PrOH: H ₂ O = 4: 1). By overnight storage at 4 ° C, the crystallization of the product succeeds. This is taken up in a little MTBE and filtered through Cellite. Removal of the solvent gives pure product (1.35 g). Further product can be isolated from the filtrate by column chromatography on silica gel (CH: EE = 95: 5) (6.90 g). A total of 8.25 g (0.022 mol, 76%), taking into account excess phenol in the yield. obtained colorless, crystalline product.
Melting point: 144-145 ° C; R _F value (CH: EE = 95: 5): 0.06; ¹ H-NMR (300 MHz, CDCl ₃ ): δ = 2.31 (s, 6H, CH ₃ ), 5.80 (s, 2H, OH), 6.88 (d, ⁴ J _{H, H} = 2.1 Hz, 2H, 6- H), 7.01 (d, ⁴ _{H, H} = 2.1 Hz, 2H, 4-H); ¹³ C-NMR (75 MHz, CDCl _3): δ = 20:24 (5-CH _3), 110.94 (C-3), 125.33 (C-1), 131.44 (C-5), 131.60 (C-6), 132.58 (C-4), 147.11 (C-2).

Example 3: Anodic oxidation of 2,4-dimethylphenol on graphite electrodes with HFIP

In an undivided standard electrolysis cell with graphite anode and cathode (A = 9 cm ² ), the electrolyte consisting of 15.98 g (0.1308 mol, 52 wt .-%) of 2,4-dimethylphenol, 1.00 g (4.4 mmol, 1 wt. -%) Methyltriethylammoniummethylsulfat and 9 mL (47 wt .-%) hexafluoroisopropanol presented. Under galvanostatic conditions, an electrolysis is carried out at 30 ° C and a current density of 10 mA / cm ² . 9721 C (0.77 F / mol) are applied at a maximum clamping voltage of 12.8 V. After completion of the reaction, the solvent is first removed and then recovered excess phenol by short path distillation. The reaction residue is taken up in 50 ml of water and 30 ml TBME, the phases are separated and the aqueous phase is extracted again with 3 × 30 ml TBME. The combined organic phases are washed with 50 ml of water and saturated sodium chloride solution, dried over magnesium sulfate and the solvent removed under reduced pressure. The crude product is dissolved in 10 mL of toluene at 50 ° C. The slow addition of n-heptane succeeds in crystallizing the product, which is obtained by filtration and washing with a little cold n-heptane. Further product can be isolated from the filtrate by column chromatography on silica gel (CH: EE = 98: 2, then 95: 5). A total of 4.43 g (0.018 mol, 28%) of colorless, crystalline product are obtained.

Melting point: 135-136 ° C; R _F value (CH: EE = 95: 5): 0.33; ¹ H-NMR (300 MHz, CDCl ₃ ): δ = 2.29 (s, 12H, CH ₃ ), 5.01 (s, 2H, OH), 6.88 (s, 2H, 4-H), 7.01 (s, 2H, 6-H); ¹³ C-NMR (75 MHz, CDCl _3): δ = 16:14 (3-CH _3), 20:41 (5-CH _3), 122.17 (C-1), 125.16 (C-3), 128.49 (C-6) , 130.00 (C-5), 132.00 (C-4), 149.13 (C-2).

Claims (13)

1. A process for preparing biaryl alcohols, wherein substituted aryl alcohols are anodically dehydrodimerized in the presence of partially fluorinated and/or perfluorinated mediators and at least one supporting electrolyte by means of a graphite electrode and the OH group of the aryl alcohols used is bound directly to the aromatic.
2. The process according to claim 1, wherein the substituted aryl alcohols used are identical.
3. The process according to either claim 1 or 2, wherein the substituted aryl alcohols used can be monocyclic or polycyclic.
4. The process according to any of claims 1 to 3, wherein the dimerization takes place in the ortho position relative to the alcohol group of the aryl alcohols.
5. The process according to any of claims 1 to 4, wherein the mediators used are partially fluorinated and/or perfluorinated alcohols and/or acids.
6. The process according to any of claims 1 to 5, wherein 1,1,1,3,3,3-hexafluoro-isopropanol or trifluoroacetic acid is used as mediator.
7. The process according to any of claims 1 to 6, wherein supporting electrolytes selected from the group consisting of alkali metal, alkaline earth metal, tetra(C₁-C₆-alkyl)ammonium salts are used as supporting electrolytes.
8. The process according to any of claims 1 to 7, wherein the counterions of the supporting electrolytes are selected from the group consisting of sulfate, hydrogensulfate, alkylsulfates, arylsulfates, halides, phosphates, carbonates, alkylphosphates, alkylcarbonates, nitrate, alkoxides, tetrafluoroborate, hexafluorophosphate and perchlorate.
9. The process according to any of claims 1 to 8, wherein no further solvent is used for the electrolysis.
10. The process according to any of claims 1 to 9, wherein a flow cell is used for the electrolysis.
11. The process according to any of claims 1 to 10, wherein current densities of from 1 to 1000 mA/cm² are used.
12. The process according to any of claims 1 to 11, wherein the electrolysis is carried out at temperatures in the range from -20 to 60°C and atmospheric pressure.
13. The process according to any of claims 1 to 12, wherein 2,4-dimethylphenol is used as aryl alcohol.